Throughout this disclosure, various patent and technical publications are identified by an identifying citation. These citations and the publications referenced within the present specification are incorporated by reference into the present disclosure to more fully describe the state of the art to which this invention pertains.
Asthma affects 17 million individuals in the United States including 5 million children or according to US Centre for Disease Control 8.2% of the US population in 2009 and is responsible for $50 billion in medical costs. The prevalence of asthma in children has dramatically increased over the last 20 years, which will result in a heightened burden in the future. Asthma represents a profound burden on healthcare provisions estimated to be responsible for 9 million visits to healthcare providers, nearly 2 million emergency room visits and almost half a million hospitalizations. Although many aspects in the development of asthma have now been elucidated, the underlying cause is still unclear. This means that current therapeutic options for treatment rely on symptom management by reducing airway inflammation and the use of bronchiole dilators. However, these treatments may actually lead to disease exacerbation in the long run.
Allergic symptoms are clinical manifestations of an atopic, allergen-specific immune response. A central tenet in this paradigm is the deviation of allergen-responsive naïve T helper cells away from a tolerant or hypo-responsive mode towards a TH2-polarized effector pathway (characterized by secretion of TH2 cytokines, such as IL-4, IL-5, and IL-13). However, the mechanisms that underlie polarization towards a TH2 response are not fully understood but are thought to be partially dependant on the avidity of the antigen, cytokines released by antigen presenting cells and co-stimulatory/inhibitory molecule interactions. Macroautophagy (hereafter referred to as autophagy) is the intracellular process by which damaged organelles are cleared and recycled and is crucial for cellular survival to starvation (Deretic et al. (2009) Cell Host Microbe 5:527-549; Yang et al. (2009) Curr Top Microbiol Immunol 335:1-32; Yang et al. (2010) Nat Cell Biol 12:814-822). Increasing evidence now suggests that pathogens can inhibit autophagy to prevent their destruction or paradoxically may hijack autophagy to increase infectivity (Kim et al. (2010) Semin Immunopathol 32:323-341). In addition the breakdown of pathogens by autophagy is required for the generation of peptides that can be presented to the immune system to stimulate the adaptive immune system (Lee et al. (2010) Immunity 32:227-239; Paludan et al. (2005) Science 307:593-596) and release of other pathogen components, which can activate pattern recognition receptors of the innate immune system (Jounai et al. (2007) Proc Natl Acad Sci USA 104:14050-14055; Lee et al. (2007) Science 315:1398-1401). Defects in autophagy results in an inability to recycle damaged organelles with the potential release of reactive oxygen species (Tal et al. (2009) Proc Natl Acad Sci USA 106:2770-2775) and other cellular components and is also associated with impaired apoptosis and clearance of dying cells (Qu et al. (2007) Cell 128:931-946). Both of these can lead to activation of the immune system and the development of autoimmune disorders. Therefore, autophagy is a crucial cellular process for survival and in addition in the establishment of innate and adaptive immune responses (Levine et al. (2011) Nature 469:323-335).
Emerging evidence suggests that autophagy is involved in numerous aspects of human health such as infection, aging, cancer, neurodegenerative diseases and is a fundamental homeostatic mechanism that can be adaptive or maladaptive so as to promote health or disease (Yang et al. (2009) Curr Top Microbiol Immunol 335:1-32). Several recent reports suggest that autophagy is involved in cigarette smoke induced apoptosis that underlies part of the pathogenic cascade of chronic obstructive pulmonary disease (Chen et al. (2008) PLoS One 3:e3316; Chen et al. (2010) Proc Natl Acad Sci USA 107:18880-18885; Hwang et al. (2010) Arch Biochem Biophys 500:203-209; Kim et al. (2008) Autophagy 4:887-895). However, there are as yet no reports regarding the role of autophagy in the development of asthma. Interestingly, carbamazepine a FDA-approved anticonvulsant, which can induce autophagy, has been shown to improve asthma by an unknown mechanism (Lomia et al. (2006) Respir Med 100:1988-1996). Therefore a determination of the role of autophagy in the airways will provide new concepts relevant to asthma disease pathogenesis and treatment.